Alexandra Kirner - Academia.edu (original) (raw)

Papers by Alexandra Kirner

European Radiology

Objectives The aim of this study was to assess the texture of repair tissue and tissue adjacent t... more Objectives The aim of this study was to assess the texture of repair tissue and tissue adjacent to the repair site after matrix-associated chondrocyte transplantation (MACT) of the knee using gray-level co-occurrence matrix (GLCM) texture analysis of T2 quantitative maps. Methods Twenty patients derived from the MRI sub-study of multicenter, single-arm phase III study underwent examination on a 3 T MR scanner, including a T2 mapping sequence 12 and 24 months after MACT. Changes between the time points in mean T2 values and 20 GLCM features were assessed for repair tissue, adjacent tissue, and reference cartilage. Differences in T2 values and selected GLCM features between the three cartilage sites at two time points were analyzed using linear mixed-effect models. Results A significant decrease in T2 values after MACT, between time points, was observed only in repair cartilage (p < 0.001). Models showed significant differences in GLCM features between repair tissue and reference c...

CARTILAGE, 2021

Objective The aim of this study was to investigate texture features from T2 maps as a marker for ... more Objective The aim of this study was to investigate texture features from T2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures. Design Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics. Results There was no statistical significance found between MFX and MACT for T2 values ( P = 0.96). There...

Journal of Clinical Oncology, 2010

2587 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally prese... more 2587 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally presented tumor-associated peptides (9 HLA class I- and 1 HLA class II-binding peptides). A previous phase I study showed a significant correlation of disease control rates (DCR) at 3 months with T-cell responses to multiple IMA901 peptides but not to a vaccinated control peptide. Methods: 68 HLA-A*02-positive metastatic clear-cell RCC patients progressing during or after first-line cytokine or TKI therapy were randomized 1:1 to receive repeated intradermal vaccinations of IMA901 together with 75 μ g GM-CSF plus/minus a single infusion of low-dose cyclophosphamide (CY; 300mg/m2) 3 days before the first vaccination. Clinical endpoints included DCR and overall survival (OS). Immunological endpoints included peripheral blood analysis of vaccine-induced peptide-specific T-cell responses to IMA901 (multimer and ELISpot analysis), FoxP3-positive regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and se...

Journal of Clinical Oncology, 2010

4529 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally prese... more 4529 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally presented tumor-associated peptides (9 HLA-class I- and 1 HLA class II-binding peptides). A previous phase I study showed a significant correlation of disease control rate (DCR) at 3 mo with T-cell responses to multiple IMA901 peptides but no correlation to a vaccinated control peptide. Methods: HLA-A*02+ patients with clear-cell RCC and documented progression during or after first-line cytokine- or TKI-based therapy were randomized 1:1 to receive up to 17 intradermal vaccinations of IMA901 over 9 mo together with 75 μ g GM-CSF ± a single infusion of low-dose cyclophosphamide (Cy; 300 mg/m2) before the first vaccination. Stratification included MSKCC risk group (low or intermediate risk) and first-line therapy (cytokines or TKI). Primary endpoint was DCR at 6 mo. Secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and peptide-specific T-cell responses. Results: 68 patients w...

The Lancet Oncology, 2016

European Journal of Cancer, 2015

Results: 667 patients with PD-L1 TC2/3 or IC2/3 tumors were enrolled. 659 pts were treated and ev... more Results: 667 patients with PD-L1 TC2/3 or IC2/3 tumors were enrolled. 659 pts were treated and evaluable for efficacy and safety. Pts had a median age of 64 y, 35% were ECOG PS 0, 28% had squamous NSCLC and 17% never smoked. As of May 28, 2015 (data cutoff), BIRCH met its primary endpoint in all predefined subgroups. ORRs by cohort are shown (table). With a minimum follow up of 6 mo, >61% of responses were ongoing. Median treatment duration for all pts was 4.2 mo (range, 0−15). 38% of pts had an all-cause Gr 3−4 AE; 11% had a treatment-related Gr 3−4 AE. The most common related AEs were fatigue (18%) and nausea (10%). 6% of pts discontinued study treatment due to an AE (eg pneumonitis, 0.6%; pneumonia, 0.5%). One Gr 5 treatment-related event (pneumonia) occurred. Other data (eg INV assessments; EGFR mutation subgroup) will be presented. Conclusions: Within rapidly changing treatment paradigms for NSCLC, BIRCH demonstrated clinically meaningful monotherapy efficacy in pts with PD-L1-selected advanced NSCLC, with no unexpected toxicities. These data, along with other atezo NSCLC data, indicate that PD-L1 selection may provide a way to identify pts likely to benefit from treatment with atezo. Genentech; NCT02031458.

Cancer Research, 2013

Translational research and the clinical development of therapeutic cancer vaccines require strong... more Translational research and the clinical development of therapeutic cancer vaccines require strong scientific rationale in order to better understand the mode-of-action and to incorporate the lessons learned in the optimization of cancer vaccines by (i) selecting appropriate immunomodulators to generate more effective vaccine regimens, (ii) combining vaccine regimens and standard-of-care therapeutics with synergistic potential and (iii) identifying patient populations that may have a better chance of responding to the vaccine. Here we demonstrate how preclinical and clinical immune response markers combined with cellular and serum biomarkers that define the immune regulatory environment were utilized as guiding tools in the development of three novel multi-peptide vaccines in renal cell cancer (IMA901), colorectal cancer (IMA910) and glioblastoma (IMA950). All three vaccine products comprise multiple tumor-associated peptides (TUMAPs) confirmed, by mass spectrometry, to be naturally ...

Human vaccines & immunotherapeutics, 2014

Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction... more Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction of targeted agents such as multi-kinase inhibitors, long-term benefits are still limited and a significant unmet medical need remains for this disease. Cancer immunotherapy has shown its potential by the induction of long-lasting responses in a small subset of patients, however, the unspecific immune interventions with (high dose) cytokines used so far are associated with significant side effects. Specific cancer immunotherapy may circumvent these problems by attacking tumor cells while sparing normal tissue with the use of multi-peptide vaccination being one of the most promising strategies. We here summarize the clinical and translational data from phase I and II trials investigating IMA901. Significant associations of clinical benefit with detectable T cell responses against the IMA901 peptides and encouraging survival data in treated patients has prompted the start of a randomized, ...

Supportive Cancer Therapy, 2007

Background: Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcem... more Background: Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcemia. Osteolytic destruction is caused by the activation of osteoclasts by release of tumor-derived stimulating factors. Bisphosphonates are known to inhibit osteoclast function and, therefore, to alleviate the adverse effects of tumor-induced bone resorption. Patients and Methods: We investigated the effects of zoledronic acid on bone pain and use of analgesic medication in 604 patients with cancer with bone metastases in an openlabel multicenter study over 1 year. Patients were treated with a maximum of 12 infusions (4 mg) every 3 or 4 weeks. Results: During treatment, the mean visual analog score value for pain (mm) decreased by 13.9 ± 32.3 from 37.1 ± 28.2 to 23.3 ± 24.2 (P < .0001, t test, intent-to-treat population, n = 410) and the mean analgesic score decreased by 0.56 ± 1.42 from 1.84 ± 1.53 to 1.28 ± 1.63 (P < .0001, t test). A statistically significant reduction in visual analog score pain could be observed within 1 week after initiation of treatment. Application of zoledronic acid was safe and well tolerated. Conclusion: Treatment with zoledronic acid in patients with cancer with bone metastases in a broad range of tumor types provides substantial benefit in terms of pain relief.

Nature Medicine, 2012

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-... more IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

Cancer Research, 2011

IMA901 is a therapeutic cancer vaccine for the treatment of renal cell cancer patients based on t... more IMA901 is a therapeutic cancer vaccine for the treatment of renal cell cancer patients based on the selection of naturally presented tumor-associated peptides. A previous phase I study (N=28 patients) showed significant correlations of clinical benefit with T-cell responses to multiple IMA901 peptides. Based on this experience, a randomized phase II study was designed to explore the biological and clinical efficacy of IMA901. Different regulatory cell populations were assessed in patients prior to vaccination, including 6 phenotypically defined populations of myeloid derived suppressor cells (MDSCs). A total of 68 HLA-A*02-positive RCC patients with documented progression during or after first-line therapy with cytokines or TKI were randomized to receive or not a single infusion of low-dose cyclophosphamide (CY; 300 mg/m2) three days prior to start repeated i.d. vaccinations with IMA901 in association with 75 µg GM-CSF i.d. Among them, 64 pts were eligible according to the pre-speci...

Cancer Research, 2012

Translational research and the clinical development of therapeutic cancer vaccines requires stron... more Translational research and the clinical development of therapeutic cancer vaccines requires stronger scientific rationalization. Here we demonstrate how immune response markers as well as biomarkers defining the immune regulatory environment were utilized as guiding tools from discovery to advanced clinical trials of IMA901, a novel therapeutic vaccine for the treatment of renal cell carcinoma (RCC). IMA901 consists of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human RCC tissue by mass spectrometry, selected using differential transcriptomics and preclinically validated by systematic analysis of immunogenicity with artificial antigen-presenting cells. Two consecutive independent clinical studies in a total of 96 HLA-A*02+ advanced/metastatic RCC patients were conducted. The phase I study revealed that T-cell responses to multiple IMA901 antigens were significantly associated with disease control and negatively associated with the presence of F...

Behavioural Processes, 1999

Olfaction is one of the most important sensory systems for many mammalian species. Yet, the exten... more Olfaction is one of the most important sensory systems for many mammalian species. Yet, the extent to which olfactory stimuli control the behaviour of a specific species is difficult to establish. Traditionally, massive invasive techniques like destruction of the olfactory sensory epithelium or bulbectomy are applied to estimate the effect of olfactory stimuli. However, for behavioural research less invasive methods are required. Application of lectins to the olfactory epithelium seems to be a promising new approach to study the releasing effect of odours on behaviour. This new approach is demonstrated in 30 adult male Wistar rats for the lectins Concanavalin A, lotus tetragonolobus and wheat germ agglutinin. Rats were trained to detect low concentrations of ethyl acetate, 1-methyl naphthalene or methacrylic acid. The lectins applied to the olfactory mucosa had selective inhibitory effects on odour detection; in each case detection inhibition was reversible within 4-48 h after lectin application. These results provide behavioural evidence for odour-specific inhibition without destruction to the animal. This new approach is discussed with the traditional invasive techniques use to inhibit odour detection.

Behavioural Brain Research, 2003

Carvone enantiomers (D and L optical isomers) have been shown to be discriminable by humans even ... more Carvone enantiomers (D and L optical isomers) have been shown to be discriminable by humans even though the odor qualities are quite similar. Our experiment is based on a finding (J. Steroid Biochem. Molec. Biol. 1991;39(4B):621) that Concanavalin A (ConA) applied to a frog olfactory epithelium preparation blocks cAMP transduction induced by D-but not by L-carvone. We used standard operant conditioning methods to train animals to discriminate low odor concentrations of D-carvone from clean air, to discriminate L-carvone from clean air; or to discriminate between clean air and the odors of D-carvone, L-carvone, ethyl acetate and methacrylic acid. After perfusion of the nasal cavity with ConA, rats did not respond to D-carvone above or near chance level, while the L-carvone response was not affected at the same or higher ConA doses. However, for rats trained on both enantiomers and the two other unrelated odorants, the D-carvone response remained unaffected by ConA. These results suggest to us that: (1) ConA blocks at least one chiral receptor selective for D-carvone; (2) D-carvone odor quality is modified by ConA so that it is no longer recognized by rats trained on D-carvone only, while rats trained to generalize odors still respond to D-carvone.

European Radiology

Objectives The aim of this study was to assess the texture of repair tissue and tissue adjacent t... more Objectives The aim of this study was to assess the texture of repair tissue and tissue adjacent to the repair site after matrix-associated chondrocyte transplantation (MACT) of the knee using gray-level co-occurrence matrix (GLCM) texture analysis of T2 quantitative maps. Methods Twenty patients derived from the MRI sub-study of multicenter, single-arm phase III study underwent examination on a 3 T MR scanner, including a T2 mapping sequence 12 and 24 months after MACT. Changes between the time points in mean T2 values and 20 GLCM features were assessed for repair tissue, adjacent tissue, and reference cartilage. Differences in T2 values and selected GLCM features between the three cartilage sites at two time points were analyzed using linear mixed-effect models. Results A significant decrease in T2 values after MACT, between time points, was observed only in repair cartilage (p < 0.001). Models showed significant differences in GLCM features between repair tissue and reference c...

CARTILAGE, 2021

Objective The aim of this study was to investigate texture features from T2 maps as a marker for ... more Objective The aim of this study was to investigate texture features from T2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures. Design Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics. Results There was no statistical significance found between MFX and MACT for T2 values ( P = 0.96). There...

Journal of Clinical Oncology, 2010

2587 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally prese... more 2587 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally presented tumor-associated peptides (9 HLA class I- and 1 HLA class II-binding peptides). A previous phase I study showed a significant correlation of disease control rates (DCR) at 3 months with T-cell responses to multiple IMA901 peptides but not to a vaccinated control peptide. Methods: 68 HLA-A*02-positive metastatic clear-cell RCC patients progressing during or after first-line cytokine or TKI therapy were randomized 1:1 to receive repeated intradermal vaccinations of IMA901 together with 75 μ g GM-CSF plus/minus a single infusion of low-dose cyclophosphamide (CY; 300mg/m2) 3 days before the first vaccination. Clinical endpoints included DCR and overall survival (OS). Immunological endpoints included peripheral blood analysis of vaccine-induced peptide-specific T-cell responses to IMA901 (multimer and ELISpot analysis), FoxP3-positive regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and se...

Journal of Clinical Oncology, 2010

4529 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally prese... more 4529 Background: IMA901 is a therapeutic cancer vaccine based on the selection of naturally presented tumor-associated peptides (9 HLA-class I- and 1 HLA class II-binding peptides). A previous phase I study showed a significant correlation of disease control rate (DCR) at 3 mo with T-cell responses to multiple IMA901 peptides but no correlation to a vaccinated control peptide. Methods: HLA-A*02+ patients with clear-cell RCC and documented progression during or after first-line cytokine- or TKI-based therapy were randomized 1:1 to receive up to 17 intradermal vaccinations of IMA901 over 9 mo together with 75 μ g GM-CSF ± a single infusion of low-dose cyclophosphamide (Cy; 300 mg/m2) before the first vaccination. Stratification included MSKCC risk group (low or intermediate risk) and first-line therapy (cytokines or TKI). Primary endpoint was DCR at 6 mo. Secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and peptide-specific T-cell responses. Results: 68 patients w...

The Lancet Oncology, 2016

European Journal of Cancer, 2015

Results: 667 patients with PD-L1 TC2/3 or IC2/3 tumors were enrolled. 659 pts were treated and ev... more Results: 667 patients with PD-L1 TC2/3 or IC2/3 tumors were enrolled. 659 pts were treated and evaluable for efficacy and safety. Pts had a median age of 64 y, 35% were ECOG PS 0, 28% had squamous NSCLC and 17% never smoked. As of May 28, 2015 (data cutoff), BIRCH met its primary endpoint in all predefined subgroups. ORRs by cohort are shown (table). With a minimum follow up of 6 mo, >61% of responses were ongoing. Median treatment duration for all pts was 4.2 mo (range, 0−15). 38% of pts had an all-cause Gr 3−4 AE; 11% had a treatment-related Gr 3−4 AE. The most common related AEs were fatigue (18%) and nausea (10%). 6% of pts discontinued study treatment due to an AE (eg pneumonitis, 0.6%; pneumonia, 0.5%). One Gr 5 treatment-related event (pneumonia) occurred. Other data (eg INV assessments; EGFR mutation subgroup) will be presented. Conclusions: Within rapidly changing treatment paradigms for NSCLC, BIRCH demonstrated clinically meaningful monotherapy efficacy in pts with PD-L1-selected advanced NSCLC, with no unexpected toxicities. These data, along with other atezo NSCLC data, indicate that PD-L1 selection may provide a way to identify pts likely to benefit from treatment with atezo. Genentech; NCT02031458.

Cancer Research, 2013

Translational research and the clinical development of therapeutic cancer vaccines require strong... more Translational research and the clinical development of therapeutic cancer vaccines require strong scientific rationale in order to better understand the mode-of-action and to incorporate the lessons learned in the optimization of cancer vaccines by (i) selecting appropriate immunomodulators to generate more effective vaccine regimens, (ii) combining vaccine regimens and standard-of-care therapeutics with synergistic potential and (iii) identifying patient populations that may have a better chance of responding to the vaccine. Here we demonstrate how preclinical and clinical immune response markers combined with cellular and serum biomarkers that define the immune regulatory environment were utilized as guiding tools in the development of three novel multi-peptide vaccines in renal cell cancer (IMA901), colorectal cancer (IMA910) and glioblastoma (IMA950). All three vaccine products comprise multiple tumor-associated peptides (TUMAPs) confirmed, by mass spectrometry, to be naturally ...

Human vaccines & immunotherapeutics, 2014

Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction... more Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction of targeted agents such as multi-kinase inhibitors, long-term benefits are still limited and a significant unmet medical need remains for this disease. Cancer immunotherapy has shown its potential by the induction of long-lasting responses in a small subset of patients, however, the unspecific immune interventions with (high dose) cytokines used so far are associated with significant side effects. Specific cancer immunotherapy may circumvent these problems by attacking tumor cells while sparing normal tissue with the use of multi-peptide vaccination being one of the most promising strategies. We here summarize the clinical and translational data from phase I and II trials investigating IMA901. Significant associations of clinical benefit with detectable T cell responses against the IMA901 peptides and encouraging survival data in treated patients has prompted the start of a randomized, ...

Supportive Cancer Therapy, 2007

Background: Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcem... more Background: Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcemia. Osteolytic destruction is caused by the activation of osteoclasts by release of tumor-derived stimulating factors. Bisphosphonates are known to inhibit osteoclast function and, therefore, to alleviate the adverse effects of tumor-induced bone resorption. Patients and Methods: We investigated the effects of zoledronic acid on bone pain and use of analgesic medication in 604 patients with cancer with bone metastases in an openlabel multicenter study over 1 year. Patients were treated with a maximum of 12 infusions (4 mg) every 3 or 4 weeks. Results: During treatment, the mean visual analog score value for pain (mm) decreased by 13.9 ± 32.3 from 37.1 ± 28.2 to 23.3 ± 24.2 (P < .0001, t test, intent-to-treat population, n = 410) and the mean analgesic score decreased by 0.56 ± 1.42 from 1.84 ± 1.53 to 1.28 ± 1.63 (P < .0001, t test). A statistically significant reduction in visual analog score pain could be observed within 1 week after initiation of treatment. Application of zoledronic acid was safe and well tolerated. Conclusion: Treatment with zoledronic acid in patients with cancer with bone metastases in a broad range of tumor types provides substantial benefit in terms of pain relief.

Nature Medicine, 2012

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-... more IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

Cancer Research, 2011

IMA901 is a therapeutic cancer vaccine for the treatment of renal cell cancer patients based on t... more IMA901 is a therapeutic cancer vaccine for the treatment of renal cell cancer patients based on the selection of naturally presented tumor-associated peptides. A previous phase I study (N=28 patients) showed significant correlations of clinical benefit with T-cell responses to multiple IMA901 peptides. Based on this experience, a randomized phase II study was designed to explore the biological and clinical efficacy of IMA901. Different regulatory cell populations were assessed in patients prior to vaccination, including 6 phenotypically defined populations of myeloid derived suppressor cells (MDSCs). A total of 68 HLA-A*02-positive RCC patients with documented progression during or after first-line therapy with cytokines or TKI were randomized to receive or not a single infusion of low-dose cyclophosphamide (CY; 300 mg/m2) three days prior to start repeated i.d. vaccinations with IMA901 in association with 75 µg GM-CSF i.d. Among them, 64 pts were eligible according to the pre-speci...

Cancer Research, 2012

Translational research and the clinical development of therapeutic cancer vaccines requires stron... more Translational research and the clinical development of therapeutic cancer vaccines requires stronger scientific rationalization. Here we demonstrate how immune response markers as well as biomarkers defining the immune regulatory environment were utilized as guiding tools from discovery to advanced clinical trials of IMA901, a novel therapeutic vaccine for the treatment of renal cell carcinoma (RCC). IMA901 consists of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human RCC tissue by mass spectrometry, selected using differential transcriptomics and preclinically validated by systematic analysis of immunogenicity with artificial antigen-presenting cells. Two consecutive independent clinical studies in a total of 96 HLA-A*02+ advanced/metastatic RCC patients were conducted. The phase I study revealed that T-cell responses to multiple IMA901 antigens were significantly associated with disease control and negatively associated with the presence of F...

Behavioural Processes, 1999

Olfaction is one of the most important sensory systems for many mammalian species. Yet, the exten... more Olfaction is one of the most important sensory systems for many mammalian species. Yet, the extent to which olfactory stimuli control the behaviour of a specific species is difficult to establish. Traditionally, massive invasive techniques like destruction of the olfactory sensory epithelium or bulbectomy are applied to estimate the effect of olfactory stimuli. However, for behavioural research less invasive methods are required. Application of lectins to the olfactory epithelium seems to be a promising new approach to study the releasing effect of odours on behaviour. This new approach is demonstrated in 30 adult male Wistar rats for the lectins Concanavalin A, lotus tetragonolobus and wheat germ agglutinin. Rats were trained to detect low concentrations of ethyl acetate, 1-methyl naphthalene or methacrylic acid. The lectins applied to the olfactory mucosa had selective inhibitory effects on odour detection; in each case detection inhibition was reversible within 4-48 h after lectin application. These results provide behavioural evidence for odour-specific inhibition without destruction to the animal. This new approach is discussed with the traditional invasive techniques use to inhibit odour detection.

Behavioural Brain Research, 2003

Carvone enantiomers (D and L optical isomers) have been shown to be discriminable by humans even ... more Carvone enantiomers (D and L optical isomers) have been shown to be discriminable by humans even though the odor qualities are quite similar. Our experiment is based on a finding (J. Steroid Biochem. Molec. Biol. 1991;39(4B):621) that Concanavalin A (ConA) applied to a frog olfactory epithelium preparation blocks cAMP transduction induced by D-but not by L-carvone. We used standard operant conditioning methods to train animals to discriminate low odor concentrations of D-carvone from clean air, to discriminate L-carvone from clean air; or to discriminate between clean air and the odors of D-carvone, L-carvone, ethyl acetate and methacrylic acid. After perfusion of the nasal cavity with ConA, rats did not respond to D-carvone above or near chance level, while the L-carvone response was not affected at the same or higher ConA doses. However, for rats trained on both enantiomers and the two other unrelated odorants, the D-carvone response remained unaffected by ConA. These results suggest to us that: (1) ConA blocks at least one chiral receptor selective for D-carvone; (2) D-carvone odor quality is modified by ConA so that it is no longer recognized by rats trained on D-carvone only, while rats trained to generalize odors still respond to D-carvone.